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Resistance to sorafenib, an effective first-line treatment for advanced hepatocellular carcinoma (HCC), greatly compromised the prognosis of patients. The extracellular matrix is one of the most abundant components of the tumor microenvironment. Beyond acting as a physical barrier, it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance. With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation, we discovered that fibronectin extra domain A (FN-EDA) derived from cancer-associated fibroblasts played a critical role in sorafenib resistance. Mechanistically, FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway, thereby countering the oxidative stress induced by sorafenib. Moreover, we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model, which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues, and through the analysis of HCC samples obtained from The Cancer Genome Atlas (TCGA) database. Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.
Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochim Biophys Acta Rev Cancer. 2020;1873(1):188314.
Liu Z, Lin Y, Zhang J, et al. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):447.
Najafi M, Farhood B, Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem. 2019;120(3):2782–2790.
Yu S, Yu X, Sun L, et al. GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway. Oncogene. 2020;39(27):5042–5055.
Rybak JN, Roesli C, Kaspar M, Villa A, Neri D. The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Res. 2007;67(22):10948–10957.
Ou JJ, Wu F, Liang HJ. Colorectal tumor derived fibronectin alternatively spliced EDA domain exserts lymphangiogenic effect on human lymphatic endothelial cells. Cancer Biol Ther. 2010;9(3):186–191.
Ou J, Li J, Pan F, et al. Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin α9. J Cell Biochem. 2011;112(8):2106–2114.
Liu X, Pei C, Yan S, et al. NADPH oxidase 1-dependent ROS is crucial for TLR4 signaling to promote tumor metastasis of non-small cell lung cancer. Tumour Biol. 2015;36(3):1493–1502.
Li AM, Ye J. Reprogramming of serine, glycine and one-carbon metabolism in cancer. Biochim Biophys Acta, Mol Basis Dis. 2020;1866(10):165841.
Hebbring SJ, Chai Y, Ji Y, et al. Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization. J Neurochem. 2012;120(6):881–890.
Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16(10):650–662.
Paone A, Marani M, Fiascarelli A, et al. SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation. Cell Death Dis. 2014;5(11):e1525.
Dou C, Xu Q, Liu J, et al. SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production. J Exp Clin Cancer Res. 2019;38(1):70.
Rajak S, Hussain Y, Singh K, et al. Cellular fibronectin containing extra domain A causes insulin resistance via Toll-like receptor 4. Sci Rep. 2020;10(1):9102.
Eun JW, Yoon JH, Ahn HR, et al. Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib. Cancer Commun. 2023;43(4):455–479.
Micke P, Ostman A. Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy. Expert Opin Ther Targets. 2005;9(6):1217–1233.
Chen X, Wu T, Xian L, et al. circGLS2 inhibits hepatocellular carcinoma recurrence via regulating hsa-miR-222-3p-PTEN-AKT signaling. Signal Transduct Targeted Ther. 2023;8(1):67.
Mirzaei S, Saghari S, Bassiri F, et al. NF-κB as a regulator of cancer metastasis and therapy response: a focus on epithelial-mesenchymal transition. J Cell Physiol. 2022;237(7):2770–2795.
Efthymiou G, Saint A, Ruff M, Rekad Z, Ciais D, Van Obberghen-Schilling E. Shaping up the tumor microenvironment with cellular fibronectin. Front Oncol. 2020;10:641.
Bordeleau F, Califano JP, Negrón Abril YL, et al. Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors. Proc Natl Acad Sci USA. 2015;112(27):8314–8319.
Kwon A, Chae IH, You E, et al. Extra domain A-containing fibronectin expression in Spin90-deficient fibroblasts mediates cancer-stroma interaction and promotes breast cancer progression. J Cell Physiol. 2020;235(5):4494–4507.
Mitchell S, Vargas J, Hoffmann A. Signaling via the NF-κB system. Wiley Interdiscip Rev Syst Biol Med. 2016;8(3):227–241.
Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001;276(13):10229–10233.
Ma L, Wang L, Khatib SA, et al. Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Hepatol. 2021;75(6):1397–1408.
Lee WD, Pirona AC, Sarvin B, et al. Tumor reliance on cytosolic versus mitochondrial one-carbon flux depends on folate availability. Cell Metabol. 2021;33(1):190–198.e6.
Chang YS, Su CW, Chen SC, Chen YY, Liang YJ, Wu JC. Upregulation of USP22 and ABCC1 during sorafenib treatment of hepatocellular carcinoma contribute to development of resistance. Cells. 2022;11(4):634.
Chen X, Song E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov. 2019;18(2):99–115.
Walker C, Mojares E, Del Río Hernández A. Role of extracellular matrix in development and cancer progression. Int J Mol Sci. 2018;19(10):3028.
Xu J, Ji L, Ruan Y, et al. UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma. Signal Transduct Targeted Ther. 2021;6(1):190.
Wei L, Lee D, Law CT, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun. 2019;10(1):4681.
Martín-Masot R, Mota-Martorell N, Jové M, Maldonado J, Pamplona R, Nestares T. Alterations in one-carbon metabolism in celiac disease. Nutrients. 2020;12(12):3723.
Dhanesha N, Chorawala MR, Jain M, et al. Fn-EDA (fibronectin containing extra domain A) in the plasma, but not endothelial cells, exacerbates stroke outcome by promoting thrombo-inflammation. Stroke. 2019;50(5):1201–1209.
Martín-Otal C, Lasarte-Cia A, Serrano D, et al. Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells. J Immunother Cancer. 2022;10(8):e004479.
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